Project Summary/ Abstract Surgery is the only effective treatment for cataract, the most common cause of blindness worldwide. Although cataract surgery is routine and generally considered safe, it is costly and carries risks of serious complications (e.g., capsular opacification or rupture). Thus, there is a high demand for an effective topical treatment that can prevent this debilitating disease. Cataract is caused by the aggregation of lens proteins, which is associated with accumulated oxidative damage that occurs throughout one?s lifetime. Glutathione (GSH), the most important endogenous redox regulator, is highly concentrated in the lens and protects against oxidative damage. However, levels of GSH in the lens decrease with age, leaving the lens vulnerable to oxidative damage. Antioxidants that can penetrate ocular tissue have the potential to protect the lens proteins and to restore GSH. 2- Mercaptopropionylglycine (MPG), also known as tiopronin, is a thiol antioxidant drug that appears to exhibit anticataract activity. However, its ability to penetrate ocular tissues when administered in eye drop form is limited. To overcome this problem, we will investigate a novel nanodiamond (ND) drug delivery vehicle for ocular administration of MPG. The reasons for ND use are three-fold: (1) NDs can improve ocular uptake of topically administered drugs by providing sustained release on the corneal surface, (2) NDs have been shown to enhance antioxidant activity and suppress photodegradation of the adsorbed molecules, thereby protecting MPG from premature oxidation and inactivation, and (3) NDs are excellent drug delivery platforms: they are non-toxic and chemically stable, while also exhibiting large surface area-to-mass and highly tailorable surface chemistry for optimization of interactions with drugs and tissues at their intended destination. The project?s long-term goal is to develop a topically applied formulation that can halt or significantly delay progression of cataracts. The Specific Aims of this proposed research are (1) to determine the optimal surface chemistry of the novel nanodiamond (ND) drug delivery platform for enhancing corneal penetration of MPG, (2) to determine whether NDs can preserve or promote the antioxidant efficacy of MPG, and (3) to investigate the efficacy of NDs for promoting the anticataract effects of MPG in vivo. We will characterize NDs with various surface chemistries and test their ability to deliver MPG using in vitro models of corneal and lens epithelium. We will also investigate antioxidant properties and photostability of NDs alone and in complexes with MPG in both in vitro models. To accomplish the third aim, we will use the Emory mouse, a model of age-related nuclear cataracts, which will be treated with eye drops containing MPG adsorbed to NDs prior to cataract development. We will evaluate the ability of ND-MPG eye drops to prevent cataracts by monitoring cataract formation via slit- lamp microscopy during treatment. Levels of MPG and its metabolite 2-mercaptopropionic acid (MPA), will be measured in tear fluid and ocular tissues to determine the extent of drug release and penetration. Various markers of oxidative stress including GSH/GSSG ratio, antioxidant enzyme activities, and lipid peroxidation will be measured in the ocular tissues to determine if ND improve antioxidant activity of MPG.